The invention relates to the field of organ transplantation. In particular, the present invention relates to methods for helping to prevent rejection of organ transplants by the recipient. The present invention also relates to pharmaceutical compositions for helping to prevent rejection of organ transplants by treatment of the donor.
Throughout the brief history of organ transplant surgery, included in the broader term xe2x80x9callograftxe2x80x9d, research has rapidly progressed to the point where many transplant surgeries are now considered routine procedures. In fact, we have moved from the time of the first successful organ transplant in just the latter half of this century to the point where, for example kidney transplants, are considered somewhat routine. However, in spite of the frequency with which organ transplants are now carried out, great hurdles remain to be overcome.
After transplant surgery, the greatest challenge for physicians is to prevent graft rejection by the recipient""s immune system and to prevent infections caused by the immunosuppressant treatment of the recipient. Immune response of an organ transplant recipient includes activation of the recipient""s T-cells. Immune systems of animals are designed such that they help to protect the body by attacking anything in the body that the body does not recognize. In this way, immune systems help to combat foreign bodies, such as viruses and bacteria that find their way into a body.
In the same manner that a virus or bacteria represents a foreign substance to a body""s immune system, an organ from a donor represents foreign matter to the immune system of the recipient. No matter how well the characteristics of the recipient and the donor match, such as blood groups and other histocompatibility factors, organ transplant will still act as a foreign substance for the purposes of inducing an immune response in a recipient""s body. As stated above, the immune response to an organ transplant, typically referred to as an allograft, includes the activation of T-cells.
As a result, after transplantation, it is necessary that the immune system of the recipient be controlled as much as possible to prevent graft rejection. Currently, the success of organ transplant surgery is highly dependent on an immunosuppression regimen initiated at the time or before transplantation. Such immune suppressing activity must continue for the remainder of the patient""s life. Typically, conventual immunosuppression therapy includes at least one immunosuppressing drug administered to the recipient. These drugs include Cyclosporine, Azathioprine, steroids, Tacrolimus, and/or Mycophenolate Mofetil. Any one or more of these drugs may be administered individually or in combination, simultaneously or successively to suppress immune response in the recipient""s body. These drugs act non specifically and broadly impair the recipient""s immune system to reduce the immune response against the graft.
Typically, even with the use of immunosuppressants, patients have a risk of about 5% to about 20% per year of losing grafts during the first three years following transplantation. Furthermore, less than 50% of patients receiving organs from unrelated donors have functioning grafts after 10 years. Along these lines, there have been well publicized cases of patients requiring multiple transplant surgeries as their bodies reject graft after graft.
Not only do patients risk rejection of organ transplants, but inherent in the term xe2x80x9cimmunosuppressingxe2x80x9d drugs is the fact that the drugs suppress the immune systems of the patients. As a result, transplant patients are more susceptible to contracting infections. This may be particularly damaging to transplant patients in the time just after receiving the transplanted organ since the patients will also be weak as a result of undergoing major surgery. Additionally, at this time, it is desired for transplant patients to heal. In other words, it is desired that the transplant recipient""s body expend energy in healing and incorporating the transplanted organ into the body rather than fighting to reject the organ or fighting infections resulting from a compromised immune system. Moreover, one should keep in mind that infection is a major cause of death at anytime after transplant because the recipient must always take immunosuppressive drugs.
The present invention provides a method for addressing the above-described as well as other problems by providing a treatment that reduces graft rejection. The present invention may also result in eliminating or reducing immunosuppressing compounds that must be administered to a patient, thus significantly reducing the patient""s susceptibility to infection.
In accordance with these and other objects and advantages, an aspect of the present invention provides a method for treating an organ donor prior to harvesting organ to reduce graft rejection in a recipient and a method for reducing acute allograft graft rejection. According to these methods, an amount effective to reduce graft rejection of at least one compound selected from the group consisting of compounds having formulas I, II, III, IV, V, VI, and VII is administered to an organ donor: 
wherein
Y is 
X is F or Cl;
R1 is a straight or branched alkyl group having from 1 to 7 carbon atoms;
R2 is a straight or branched alkyl group having from 1 to 7 carbon atoms;
R3 is H or a straight or branched alkyl group having from 1 to 7 carbon atoms;
Z is H, OH, or a straight or branched alkyl group including from 1 to 7 carbon atoms; and
in Formula II, the OH groups may be substituted anywhere except where Y is present and are not on the same carbon atom;
in Formula III, the OH group may be substituted anywhere except where Y is present;
in Formula IV, the OH group may be substituted anywhere except where Y is present;
in Formula V, Z may be substituted anywhere except at C-1, C-6, and C-4 if Z is OH;
in Formula VI, Z may be substituted anywhere except at C-1, C-3, and C-5 if Z is OH; and
in Formula VII, Z may be at C-1, C-2, and C-3 except not on C-1 if Z is OH.
Additional aspects of the present invention provide a pharmaceutical composition that includes an amount effective to reduce graft rejection of at least one compound selected from the group consisting of compounds having the above formulas I, II, III, IV, V, VI, and VII.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.